Long-acting steroids of the estrogenic series

ABSTRACT

C7-C29 17-cycloalkenyl ethers of estradiol 3-benzoate or substituted benzoate having prolonged contraceptive and estrogenic activity are obtained by reacting estradiol 3-benzoate or substituted benzoate with a functional derivative of a cyclic ketone at a temperature higher than 70* C.

United States Patent Alberto Ercoli Milan;

Rinaldo Gardi, Carate Brianza (Milan); Romano Vitali, Casatenovo (Como), all of [72] Inventors Dec. 11, 1968, Italy, No. 24886 A/68; July 25, 1969, Italy, No. 20105 M69; July 25, 1965, Italy, No. 20106 A/69 [54] LONG-ACTING STEROIDS OF THE ESTROGENIC SERIES 42 Claims, No Drawings [52] U.S.Cl 260/3975, 260/397.4, 260/999 [5 1 Int. Cl C07c 169/08 [50] Field of Search Machine Searched Steroids; 260/3975 [56] References Cited UNITED STATES PATENTS 3,135,744 6/1964 Ercolietal. 260/239.55 3.242.198 3/1966 Ercoli et al. 260/3974 3,417,183 12/1968 Ercolietal. 424/243 Primary Examiner-Henry Av French Attorneys-Albert H. Graddis. Henry E. Millson, Jr. and

Frank S. Chow ABSTRACT: C -C 17-cycloalkenyl ethers of estradiol 3- benzoate or substituted benzoate having prolonged contraceptive and estrogenic activity are obtained by reacting estrudiol 3-benzoate or substituted benzoate with a functional derivative ofa cyclic ketone at a temperature higher than 70 C.

LONG-ACTING STEROIDS OF THE ESTROGENIC SERIES This invention relates to novel long-acting steroids of the es trogenic series. More particularly, this invention relates to C C29 l7-cycloalkenyl ethers. of estradiol 3 -benzoate and to novel compositions having prolonged contraceptive and estrogenic activity containing said C -C l7-cycloalkenyl ethers of estradiol 3-benzoate as active ingredients.

The novel compounds of the present invention are characterized by the following general formula GHQ-CH! wherein R is selected from the group consisting of hydrogen, halogen, a lower alkyl, lower alkoxy, cycloalkoxy and nitro group, n is an integer of from I to 23 inclusive.

With the term lower" we mean a number of carbon atoms in the molecule from I to 3 inclusive.

Typical examples of the above substituents at the benzene ring are: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, fluorine or chlorine. Particularly preferred are those compounds carrying the substituent in the paraposition of the benzene ring.

The compounds of the invention proved to possess interesting pharmacological properties which made them usefully employed as uterotrophic and contraceptive agents in warmblooded animals. They are suitable for the oral as well as for the parenteral administration. Further, thanks to their good solubility in oil, they can be easily administered in a single dose to obtain a prolonged effect.

In accordance with the invention, the new compositions having long-lasting contraceptive and estrogenic activity, contain as active ingredients the compounds of formula I in admixture with an inert solid or liquid pharmaceutical carrier.

Such compositions contain the active ingredient in an amount of from about 0.1 to about 100 mg, preferably from 0.5 to 20 mg., and may be in form of tablets, powders, capsules, ampuls or multiple dose flacons and other pharmaceutibalance. The increase of the uterus weight was considered as an index of the estrogenic activity.

The results obtained are summarized in table I in which the uterotrophic activity of some representative compounds of the invention, is compared with that of estradiol l7-enanthate, one of the most long-acting estrogenic agents known so far.

TABLE I Uterus weight (mg.) after 4 Weeks 8 weeks 12 weeks Controls 19. 5:1:6. 3 23. 0:4:1. 7 22. 51:2. 01 Estradlol 17-enanthate. 128. 54:5. 3 104. 44:10. 5 71. 3:113. 76 Estradlol B-p-chloroben 17-(1-cyclooetenyl) ether. 195. 2:|:9. 6 164. 4113. 4 142. 1:1:8. 17 Estradlol 3-p-fluorobenzoate 17-(1-cycl00ctenyl)ether 194. 34:7. 4 180. 5:1:9. 5 124. 75:8. 97 Estradlol 3-anlsate 17-(1- cyclooctenyDether 207. 9i7. 2 174. 9:t:16. 0 118. 4:1:10. Estradlol 3-benzoate 17-(1- cyclohepteny1)ether 209. :15. 7 154. 1d:11. 9 Estradl 3-benzoate 17- cyclooctenyl) ether 163. 9:}:17. 8 159. 5*14. 6 Estradlol 3-benzoate 17-(1- cyclononenyl) ether 208. 0:1:9. 0 162. 0i12. 4 131. 6:1:8. 34 Estradlol 3-benzoate 17(1- cyclodecenyl) ether 120. 35:15. 5 138. 2*10. 2 Estradl013-benzoate 17-(1- cyclododecenyl)ether 90. 3:1:17. 2 165. 4:1:16. 6 Estradlol a-benzoate 17-(1- cyclopentadeeenyl)ether. 171. 5:]:12. 4 194. 85:9. 8 170. 4:1:15. 2 Estradlol 3-0-chlorobenzoate 17-(1-cyclooetenyl)ether 146. 03:15. 3 158. 8:1:12. 9 157. 7:1:19. 9 Estradlol 3-m-chlorobenzoate 17-(1-cyclooctenyl) ether- 163. 2:1:5. 2 165. 05:6. 8 187. 6:|:8. 1

1 Data not evaluated.

Table I shows that the compounds according to the invention exhibit an estrogenic activity greater and much more prolonged than that of the standard compound.

More particularly, it results that even l2 weeks after the treatment some of the compounds of the invention still possess an uterotrophic activity at least equal to that displayed by the standard compound at the end of the 4th week.

B. Determination of the contraceptive activity The contraceptive activity was determined in mature Wistar female rats weighing about 150-170 g. The compounds under testing, in sesame oil solution, were injected subcutaneously in a single dose of 0.5 umole and on the next day the treated animals were caged with fertile males and kept therewith till pregnant, and afterwards, on days 15-18 of pregnancy, the females were put in-single cages.

The results of this investigation are summarized in table ll, were it is indicated the situation on the lth day from the administration.

TABLE II Number oi rats- On day 160 Treated Not (day Deliv- Mispreg- Compounds administered zero) ered 1 carried Killed 2 Dead nant Controls 10 9 (27. 6) 1 Estradiol 3-p-chlorobenzoate 17-(1'-eyelooctenyl)- ether 10 10 Estradiol 3-p-fluorobenzoate 17-(1'-cyclooctenyl)- ether 1O 4 (137. 7) 6 Estradiol 3-anistate 17-(1-cyclo0ctenyl) ether. 10 5 (137. 4) 1 1 3 Estradiol 3-benzoate 17-(1-cycloheptenyl)ether- 5 Estradlol 3-benzoate 17-(1-cyclooctenyl)ether 7 Estradlol 3-benzoate 17-(1-eyclononenyl)ether 3 Estradiol B-benzoate 17-(1-eyclodeceny1)ether 5 Estradlol 3-benzoate 17-(1-cyclododecenyl)ether 10 1 In parentheses the average number of days from treatment to delivery. 2 For diflicult delivery or probable reabsorption.

cal forms suitable for the oral or the parenteral administration.

PHARMACOLOGICAL DATA A. Determination of the prolonged uterotrophic activity The compounds under testing in solution of sesame oil were administered subcutaneously in a single dose of 0.05 #mole to spayed rats weighing about 45-50 g. Groups of rats were sacrificed, respectively, at the end of the 4th 8th and 12th week from the administration, and the uterus weight of the treated animals and of the controls was determined on a torsion CHz-CH:

CHz-CII:

III

wherein n has the above stated meaning, at a temperature higher than 70 C.

The term functional derivatives" means the typical derivatives of the ketones of formula III above with lower aliphatic alcohols. Such functional derivatives are lower alkyl acetals or lower alkyl enol ethers containing from l to 3 carbon atoms as well as mixtures thereof as obtained by reaction of the free ketone with a lower alkyl orthoformate, the methyl and ethyl enol ethers and/or dimethyl and diethyl acetals being preferred.

The reaction is carried out under anhydrous conditions, preferably in the presence of an acid catalyst and in an organic solvent, such as, for example benzene, toluene, xylene or dimethylformamide. After about 1 hour the reaction is over and the end product can be isolated according to usual procedures, for example by neutralizing the catalyst, if any, evaporating the solvent and crystallizing the residue from a suitable solvent.

Also included in the present invention is the description and preparation of new estradiol 3-esters, starting materials for some of the compounds of the invention. These new estradiol 3-esters, namely the compounds of formula II in which R is selected from the group consisting of a lower alkyl, lower alkoxy, cycloalkoxy, a nitro group and an halogen atom, are prepared by treating estrone with an esterifying agent derived from a substituted benzoic acid, for example an anhydride or a chloride, under usual esterification conditions and then reducing the estrogen 3-ester thus obtained with an alkali metal hydride, for example sodium borhydride, to convert the 17- keto group into a l7B-hydroxy group.

The following examples are given to illustrate the invention without limiting it. PREPARATION I To a solution of 10 g. of estrone in I00 ml. of pyridine cooled to 0 C. there is added 5 ml. of pchlorobenzoylchloride. The reaction mixture is maintained overnight at room temperature and then poured into icewater. The precipitate, filtered off and recrystallized from a methanol-methylene chloride mixture, yields 14.2 g. of estrone 3-p-chlorobenzoate, melting at l99204 C. A pure sample of the product melts at 2 l 5-2 1 7 C.

In the same manner estrone 3-m-chlorobenzoate melting point 2l2-2l4 C.; and estrone 3-o-chlorobenzoate, melting point 2 l4-2 16 C. are obtained.

PREPARATION ll To a solution of 5 g. of estrone in 50 ml. of pyridine cooled to 0 C. there is added 3 ml. of pfluorobenzoyl chloride. The reaction mixture is maintained overnight at room temperature and then poured into ice-water. So there is obtained estrone 3- p-fluorobenzoate which after crystallization from a methanolmethylene chloride mixture melts at 2 l0-2 1 2 C.

In the same manner estrone 3-m-fluorobenzoate and estrone 3-o-fluorobenzoate are obtained. PREPARATION 111 A solution of 5 g. of estrone in 50 ml. of pyridine is cooled to 0 C. and treated with 3 ml. of p-methoxybenzoylchloride. By operating as in Preparation l estrone 3-anisate is obtained, melting point 229-23 1 C.

In the same manner estrone 3-m-methoxybenzoate and estrone 3-o'methoxybenzoate are obtained. PREPARATION lV By reacting estrone with p-nitrobenzoylchloride, pcyclopentyloxybenzoylchloride and p-toluylchloride and following the procedure set forth in Preparation l estrone pnitrobenzoate, estrone p-cyclopentyloxybenzoate and estrone p-toluate are obtained, respectively.

EXAMPLE 1 To a solution of 10 g. of estrone S-p-chlorobenzoate in 320 ml. of tetrahydrofurane is added with stirring a solution of 2 g. of sodium borhydride in 10 ml. of water. After stirring for an additional 3 hours, the mixture is treated with l0 ml. of a 10 percent solution of acetic acid and evaporated in vacuo. The residue is taken up in water, filtered off and crystallized from a methylene chloride-diethyl ether mixture to obtain 6.3 g. of estradiol 3-p-chloro-benzoate, melting point l83185 C., [a] =+52 (dioxane,c=0.5%).

ln the same manner estradiol 3-m-chlorobenzoate, melting I point 166-l69 C., [a],, +53.5 (dioxane, c=0.5 percent) and estradiol 3-o-chlorobenzoate, melting point l68l 72 C., [a],,=+55.5 (dioxane, (=05 percent) are obtained.

An anhydrous mixture of 2 g. of estradiol 3-pchlorobenzoate and 20 mg. of p-toluenesulphonic acid in 700 ml. of toluene is treated with 2 ml. of cyclooctanone methyl enol ether and then distilled over a period of about 40 minutes. After addition of several drops of pyridine to neutralize the acid catalyst, the mixture is evaporated in vacuo and the solid residue thus obtained is taken up in methanol and filtered. The product, recrystallized from a methylene chloridemethanol mixture, yields 2.13 g. of estradiol 3-pchlorobenzoate l7-( l'-cyclooctenyl)ether, melting point l72l74 C., [a],, l-47 (dioxane, c=0.5 percent).

In the same manner estradiol 3-m-chlorobenzoate l7-(l'- cyclooctenyl)ether, melting point l50-l52 C., [a] =+49.8 (dioxane, c=0.5 percent) and estradiol 3-o-chlorobenzoate 17-(1-cycl0octenyl)ether, melting point l5l-l53 C., [a] =+5 1 (dioxane, c=0.5 percent), are obtained.

EXAMPLE 2 An anhydrous mixture of 2 g. of estradiol 3-pchlorobenzoate, 3 ml. of cycloheptanone dimethyl acetal, 20 mg. of pyridine tosylate and 700 ml. of toluene is distilled over a period of about 40 minutes. The acid catalyst is then neutralized with several drops of pyridine and the mixture is concentrated in vacuo to dryness. The residue, taken up with a methylene chloride-methanol mixture, yields the estradiol 3- p-chlorobenzoate l7-(l'-cycloheptenyl)ether, melting point l56l58 C., [a],,=+53 (dioxane, c=l percent).

EXAMPLE 3 An anhydrous mixture of 2 g. of estradiol 3-pchlorobenzoate, 3 ml. of cyclononanone methyl enol ether, 20

mg. of p-toluenesulfonic acid and 800 ml. of toluene is distilled over a period of about 40 minutes. The acid catalyst is then neutralized with several drops of pyridine and the mixture is concentrated in vacuo to dryness. The residue taken up with a methylene chloride-methanol mixture yields the estradiol 3-p-chlorobenzoate l7-( 1 '-cyclononenyl)ether.

in the same manner estradiol 3-p-chlorobenzoate l7-(l'- cyclododecenyl)ether is obtained, melting point l45l47 C., [a] =-|-43 (dioxane, c=0.5 percent).

EXAMPLE 4 To a stirred solution of g. of estrone 3-p-fluorobenzoate in 320 ml. of tetrahydrofurane is added with stirring-a solution of 2 g. of sodium borhydride in 10 ml. of water. After stirring for an additional 3 hours, the mixture is treated with 10 ml. of a 10 percent solution of acetic acid and evaporated in vacuo. The residue, taken up in water, filtered off and crystallized from a methylene chloride-diethyl ether mixture, yields estradiol 3-p-fluorobenzoate, melting point 2l0-2l2 C., [a] R l-56" (dioxane, =0.5 percent).

In the same manner estradiol 3-m-fluorobenzoate, and estradiol 3-o-fiuorobenzoate are obtained.

An anhydrous mixture of 2 g. of estradiol 3-pfluorobenzoate and 20 mg. of p-toluenesulphonic acid in 700 ml. of toluene is treated with 2 ml. of cyclooctanone methyl enol ether and then distilled over a period of about 40 minutes. After addition of several drops of pyridine to neutralize the acid catalyst, the mixture is evaporated in vacuo and there is obtained a solid residue which is taken up in methanol and filtered. The product, recrystallized from a methylene chloride-methanol mixture, yields estradiol 3-pfluorobenzoate l7-( 1 -cyclooctenyl)ether, melting point 14 ll44 C., [a],,"=+48 (dioxane, c=O.5 percent).

in the same manner estradiol 3-p-fluorobenzoate l7-(l'- cyclodecenyl)ether, melting point l64l66 C., [a] =+55 (dioxane, c=0.5 percent) and estradiol 3-p-fluorobenzoate l7- (l-cyclododecenyl) ether, melting point l52154 C., [a] =+-48.5 (dioxane, c=0.5 percent) are obtained.

EXAMPLE 5 To a solution of 10 g. of estrone 3-anisate in 320 ml. of tetrahydrofurane is added with stirring a solution of 2 g. of sodium borhydride in 10 ml. of water. After stirring for an additional 3 hours, the mixture is treated with 10 ml. ofa 10 percent solution of acetic acid and evaporated in vacuo. The residue taken up in water, filtered ofi and crystallized from a methylene chloridediethyl ether mixture, yields estradiol 3- anisate, melting point l95l97 C., [a],,=+53 (dioxane, c=0.5 percent).

In the same manner estradiol 3-mmethoxybenzoate, and estradiol 3-o-methoxybenzoate are obtained.

An anhydrous mixture of 2 g. of estradiol 3-anisate and 20 mg. of p-toluenesulphonic acid in 700 ml. of toluene is treated with 2 ml. of cyclooctanone methyl enol ether and then distilled over a period of about 40 minutes. After addition of several drops of pyridine to neutralize the acid catalyst, the mixture is evaporated in vacuo and there is obtained a solid residue which is taken up in methanol and filtered. The product, recrystallized from a methylene chloride-methanol mixture, yields estradiol 3-anisate l7-(l'-cyclooctenyl)ether, melting point l49-l5 1 C., [a],, =+48 (dioxane, c=0.5 percent).

In the same manner estradiol 3-anisate 17-( l '-cyclododecenyl)ether, melting point I l9-l2l C., [a] =+46.8 (dioxane, c#).05 percent) is obtained.

According to the method set forth above, by reducing estrone 3-p-nitrobenzoate with sodium borhydride, estradiol 3- p-nitrobenzoate is obtained, which is reacted with cyclooctanone methyl enol ether to obtain estradiol 3-p-nitrobenzoate l7(l"cyclooctenyl)ether, melting point 220-223 C., [a] =+44 (dioxane, v=l percent).

Analogously, estrone 3-p-cyclopentyloxybenzoate is reduced to estradiol 3-p-cyclopentyloxybenzoate. which is converted into estradiol 3-p-cyclopentyloxybenzoate 17-( lcyclooctenyl)ether, melting point 200-202 C., [a] =+44 (dioxane, c=l percent) by reaction with cyclooctanone methyl enol ether.

in the same manner estradiol 3-p-toluate (obtained by reduction of estrone p-toluate with NaBH,) is reacted with cyclooctanone methyl enol ether to obtain estradiol 3-p-toluate l7-(l'-cyclooctenyl)ether, melting point l64l66 C., [a],,=+5 1.5 (dioxane, r-l percent).

Analogously estradiol 3-p-toluate is reacted with cyclododecanone dimethyl acetale to obtain estradiol 3-p-toluate l7-(l'-cyclododecenyl)ether, melting point l39-l42 C., [a] =+46.3 (dioxane, c=l percent).

EXAMPLE 6 A mixture of 1.5 g. of exaltone (cyclopentadecanone), 2 cc. of methanol, 1.5 cc. of methyl orthoformate and 15 mg. of ptoluenesulfonic acid is heated at 6070 C. for 30 minutes. The reaction mixture, containing a mixture of methyl enol ether and dimethylacetal of exaltone, is treated with 5 cc. of dimethylformamide and 2.2 g. of estradiol 3-pchlorobenzoate, then it is heated under nitrogen atmosphere at about C. for 1 hour. After addition of a few drops of pyridine to neutralize the acid catalyst, the mixture is evaporated and the residue, crystallized from methanolmethylene chloride, gives estradiol 3-p-chlorobenzoate l7-( 1 -cyclopentadecenyl)ether.

In an analogous manner there are obtained the l7-(l'- cyclotridecenyl)ether, the 17-( l '-cycloeptadecenyl)ether, the l7-( 1 'A-cycloheneicosenyl )ether and the 17-( l cyclononacosenyl)ether of estradiol 3-p-chlorobenzoate.

EXAMPLE 7 An anhydrous mixture of 2 g. of estradiol 3-benzoate and 20 mg. of p-toluenesulfonic acid in 700 ml. of toluene is treated with 2 ml. of cyclooctanone methyl enol ether and then distilled over a period of about 40 minutes. After addition of several drops of pyridine to neutralize the acid catalyst, the mixture is evaporated in vacuo and the solid residue thus obtained is taken up in methanol and filtered. The product, recrystallized from a methylene chloridemethanol mixture, yields estradiol 3-benzoate 17-( l -cyclooctenyl)ether, melting point l74-l 76 C., [a] =+52 (dioxane, c=0.5 percent).

EXAMPLE 8 An anhydrous mixture of 2 g. of estradiol 3-benzoate, 3 ml. of cycloheptanone dimethyl acetal, 20 mg. of pyridine tosylate and 700 ml. of toluene is distilled over a period of about 40 minutes. The acid catalyst is then neutralized with several drops of pyridine and the mixture is concentrated in vacuo to dryness. The residue, taken up in a methylene chloridemethanol mixture, yields the estradiol 3-benzoate l7-( 1 cycloheptenyhether, melting point l49l5 1 C., [a],, "=-+5 7 (dioxane, c=0.5 percent).

in the same manner estradiol 3-benzoate l7-( l '-cyclonone nyl)ether, melting point l5ll55 C., [a] =+52.5 (dioxane, c=0.5 percent), estradiol 3-benzoate l7-(l'-cyclodecenyl)ether, melting point l49-15l C., [a],, =+57 (dioxane, c=0.5 percent), estradiol 3-benzoate 17-( l '-cyclododecenyl)ether, melting point l63-l66 C., [a],, =+5 l (dioxane, c=0.5 percent) and estradiol 3-benzoate l7-(l-cyclodocosenyl)ether, melting point l07l 10 C., [a] =+30.6 (dioxane, c=l percent), are obtained.

EXAMPLE 9 A mixture of 1.5 g. of exaltone (cyclopentadecanone), 2 cc. of methanol, 1.5 cc. of methylorthoformate and 15 mg. of ptoluenesulfonic acid is heated for 30 minutes at 60-70 C. The reaction mixture, containing a mixture of methyl enol ether and dimethylacetal of exaltone, is treated with 5 cc. of dimethylformamide and 2.2 g. of estradiol 3-benzoate, then heated under nitrogen atmosphere at about 160 C. for 1 hour. After addition of a few drops of pyridine to neutralize the acid catalyst, the mixture is evaporated and the residue, crystallized from methanol-methylene chloride, gives estradiol 3- benzoate l7-( l-cyclopentadecenyl)ether. Melting point l36-l 39 C., [a],, =*l-40.5 (dioxane, c=l percent).

In the same manner, the l7-(l-cyclotridecenyl)ether, the 17-(1'-cycloheptadecenyl)ether, the l7-(l-cycloheneicosenyl)ether. and the 17-( l-cyclononacosenyl)ether of estradiol 3-benzoate are obtained.

EXAMPLE I 500 mg. of estradiol 3-p-chlorobenzoate l7-(l-cyclooctenyl)ether is dissolved in lOO ml. of sesame oil and the solution is poured into 1 ml. ampuls so that each ampul contains 5 mg./ml. of the active substance.

EXAMPLE 1 l A solution of 200 mg. of estradiol 3-p-chlorobenzoate l7- (l'-cyclooctenyl)ether in 100 ml. of sesame oil is poured into I ml. ampuls to obtain ampuls containing 2 mg./ml. of the active substance.

EXAMPLE I2 500 mg. of estradiol 3-benzoate 17-( l '-cyclooctenyl)ether is dissolved in 100 ml. of sesame oil and the solution is poured into 1 ml. ampuls so that each ampul contains 5 mg./m1. ofthe active substance.

EXAMPLE 13 A solution of 200 mg. of estradiol 3-benzoate 17-( l cyclododecenyhether in [00 ml. of sesame oil is poured into 1 ml. ampuls to obtain ampuls containing 2 mg./ml. of the active substance.

We claim:

1. A compound of the formula CHz-CHZ wherein R is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, cycloalkoxy and nitrogroup and n is an integer of from 1 to 23 inclusive.

2. A compound according to claim 1 in which R is in para position of the benzene ring.

3. A compound according to claim 2 in which R is selected from the group consisting of chloro, fluoro and methoxy.

4. A compound according to claim 1 in which n is 7.

5. A compound according to claim 1 in which n is 8.

6. A compound according to claim 1 in which n is 9.

7. A compound according to claim 1 in which n is 10.

8. A compound according to claim 1 in which n is 12.

9. A compound according to claim 1 in which n is 15.

10. Estradiol 3-p-chlorobenzoate l 7-( l '-cycl0octen yl )ether.

1 l. Estradiol 3-m-chlorobenzoate l7-( 1 -cyclooctenyl)ether.

l2. Estradiol 3-o-chlorobenzoate l7-( l -cyclooctenyl)ether.

l3. Estradiol 3-p-chlorobenzoate l7-( 1 '-cycloheptenyl)ether.

l4. Estradiol 3-p-chlorobenzoate l7-( 1 '-cyclononenyl)ether.

l5. Estradiol 3-p-chlorobenzoate l7-( l'-cyclododecenyl)ether.

16. Estradiol 3-p-fluorobenzoate l7-( 1 '-cyclooctenyl)ether.

17. Estradiol 3-p-fluorobenzoate l7-( l '-cyclodecenyl)ether.

l8. Estradiol 3-p-fluorobenzoate l7-( 1 '-cyclododecenyl)ether.

19. Estradiol 3-anisate l7-( 1'-cyclooctenyl )ether.

20. Estradiol 3-anisate 17-( l '-cyclododecenyl)ether.

21. Estradiol 3-p-nitrobenzoate l7-( 1 '-cyclooctenyl)ether.

22. Estradiol 3-pcyclopentyloxybenzoate l7-( l-cyclooctenyl)ether.

23. Estradiol 3-p-toluate l7-( 1 '-cyclooctenyl)ether.

24. Estradiol 3-p-chlorobenzoate l7-(l'-cyclopentadecenyl)ether.

25. Estradiol 3-p-chlorobenzoate 17-(l'-cyclotridecenyl)ether.

26. Estradiol 3-p-chlorobenz0ate l7-(l'-cycloheptadecenyl)ether.

27. Estradiol 3-p-chlorobenzoate l7-(l'-cycloheneicosenyl)ether.

28. Estradiol 3-p-chlorobenzoate l7-(l-cyclononacosenyl)ether.

wherein R is selected from the group consisting of a lower alkyl, lower alkoxy, a cycloalkoxy, nitrogroup and an halogen atom, n is an integer of from 1 to 6 inclusive.

42. A compound of formula CHz-CH:

wherein n is an integer of from 1 to 6 inclusive.

P nt N 3,624,112 Dated November 30, 1971 Alberto Ercoli, Rinaldo Gardi, and Romano Vitali It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

On the cover sheet "July 25, 1965, Italy, No. IA/69" I I should read Jul 25, 1969, Italy, NO. 20106 M69 Column 2, lines 51-65, the third compound reported in Table II as "Estradiol-3-anistate l7-(l'-cyclooctenyl)ether" should be ---Estradiol-3-anisate l7-(l'-cyclooctenyl)ether--- Column 6, line 36, first word, "17-- (l'-A-cycloheneicosenyl)ether" should be ----l7- (1' -cycloheneicosenyl)ether--- Column 8, Claim 42, the portion of the formula reading 000- should read C00 Signed and scaled this 11 th day of July 1972.

(SEAL) Attest EDWARD MELETCHER, JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents FORM PC4050 uscoMM-Dc eoa1e-pa9 ".5 GOVERNHENY PRINTING OFFKIE I i'. 3-33 

2. A compound according to claim 1 in which R is in para position of the benzene ring.
 3. A compound according to claim 2 in which R is selected from the group consisting of chloro, fluoro and methoxy.
 4. A compound according to claim 1 in which n is
 7. 5. A compound according to claim 1 in which n is
 8. 6. A compound according to claim 1 in which n is
 9. 7. A compound according to claim 1 in which n is
 10. 8. A compound according to claim 1 in which n is
 12. 9. A compound according to claim 1 in which n is
 15. 10. Estradiol 3-p-chlorobenzoate 17-(1''-cyclooctenyl)ether.
 11. Estradiol 3-m-chlorobenzoate 17-(1''-cyclooctenyl)ether.
 12. Estradiol 3-o-chlorobenzoate 17-(1''-cyclooctenyl)ether.
 13. Estradiol 3-p-chlorobenzoate 17-(1''-cycloheptenyl)ether.
 14. Estradiol 3-p-chlorobenzoate 17-(1''-cyclononenyl)ether.
 15. Estradiol 3-p-chlorobenzoate 17-(1''-cyclododecenyl)ether.
 16. Estradiol 3-p-fluorobenzoate 17-(1''-cyclooctenyl)ether.
 17. Estradiol 3-p-fluorobenzoate 17-(1''-cyclodecenyl)ether.
 18. Estradiol 3-p-fluorobenzoate 17-(1''-cyclododecenyl)ether.
 19. Estradiol 3-anisate 17-(1''-cyclooctenyl)ether.
 20. Estradiol 3-anisate 17-(1''-cyclododecenyl)ether.
 21. Estradiol 3-p-nitrobenzoate 17-(1''-cyclooctenyl)ether.
 22. Estradiol 3-p-cyclopentyloxybenzoate 17-(1''-cyclooctenyl)ether.
 23. Estradiol 3-p-toluate 17-(1''-cyclooctenyl)ether.
 24. Estradiol 3-p-chlorobenzoate 17-(1''-cyclopentadecenyl)ether.
 25. Estradiol 3-p-chlorobenzoate 17-(1''-cyclotridecenyl)ether.
 26. Estradiol 3-p-chlorobenzoate 17-(1''-cycloheptadecenyl)ether.
 27. Estradiol 3-p-chlorobenzoate 17-(1''-cycloheneicosenyl)ether.
 28. Estradiol 3-p-chlorobenzoate 17-(1''-cyclononacosenyl)ether.
 29. Estradiol 3-benzoate 17-(1''-cyclooctenyl)ether.
 30. Estradiol 3-benzoate 17-(1''-cycloheptenyl)ether.
 31. Estradiol 3-benzoate 17-(1''-cyclononenyl)ether.
 32. Estradiol 3-benzoate 17-(1''-cyclodecenyl)ether.
 33. Estradiol 3-benzoate 17-(1''-cyclododecenyl)ether.
 34. Estradiol 3-benzoate 17-(1''-cyclopentadecenyl)ether.
 35. Estradiol 3-benzoate 17-(1''-cyclotridecenyl)ether.
 36. Estradiol 3-benzoate 17-(1''-cycloheptadecenyl)ether.
 37. Estradiol 3-benzoate 17-(1''-cycloheneicosenyl)ether.
 38. Estradiol 3-benzoate 17-(1''-cyclononacosenyl)ether.
 39. Estradiol 3-p-toluate 17-(1''-cyclododecenyl)ether.
 40. Estradiol 3-benzoate 17-(1''-cyclodocosenyl)ether.
 41. A compound of formula
 42. A compound of formula 